Abnormal accumulation and misfolding of a-synuclein (SYN) and amyloid-p protein (A|3) may be at the root of a wide spectrum of neurodegenerative disorders leading to dementia, parkinsonism, and autonomic dysfunction. These disorders, called Lewy body diseases, account for the great majority of cases with combined dementia and movement disorders in the U.S. Previously, we showed that A(31-42 enhances the aggregation and toxicity of SYN. In the previous funding period, we focused on the involvement of the lysosomal-endosomal pathway in the copathogenic synergism between A|31-42 and SYN. Our studies showed that A|31-42 and SYN promote neurodegeneration by interfering with autophagy and reducing the clearance of other neuronal proteins, such as parkin and cytoskeletal proteins. In this proposal, we we will test the hypothesis that A(31-42 activates calcium-dependent proteases in a glutamate receptor-dependent manner, which, in turn, results in the generation of SYN fragments that promote the formation of pathogenic SYN oligomers. We further hypothesize that this pathogenic cascade is engaged most readily in limbic and striatal neurons, which are particularly vulnerable to Lewy body diseases. To test these hypotheses, we propose the following specific aims. Aim 1: To determine if the coexpression of APP/A|3 and SYN affects the vulnerability of specific neuronal populations in the hippocampus and striatum (in collaboration with Project 5 and Cores C, D). Aim 2: To determine, in cultured neurons, if the copathogenic effects of A(3 and SYN depend on glutamate receptors and SYN cleavage (with Projects 1-3 and Cores B and D). Aim 3: To determine by genetic ablation whether the copathogenic effects of A[3 and SYN depend on the activation of a specific glutamate receptor in vivo (with Project 1). Aim 4: To determine if the impairments of transgenic mice expressing SYN and A(3 can be prevented or ameliorated by inhibiting glutamate receptors or promoting A(3 clearance (with Project 5 and Cores C and D). In collaboration with other components of the program, this project will help elucidate mechanisms of selective vulnerability and determine if interventions aimed at A|3 or A|3-dependent pathways might be useful in preventing or treating Lewy body diseases.